Unintended pregnancies account for almost one-half of total pregnancies in the US yearly, costing about $12 billion annually. One factor contributing to unintended pregnancies is the lack of an effective and safe oral, reversible male contraceptive drug. A promising approach for reversible suppression of spermatogenesis is antagonism of the retinoic acid receptor-alpha (RAR?). Vitamin A-deprivation is well- known to block spermatogenesis and, based on knockout animal studies, RAR? appears to be the major target of retinoic acid, the active form of Vitamin A. First-generation RAR?-selective compounds inhibited spermatogenesis in mouse but were not orally bioavailable and were only moderately selective. The ideal drug should be orally-bioavailable with 100x specificity for RAR? so that off-target effects potentially associated with antagonism of RAR? or RAR? can be minimized. We have identified highly selective RAR? antagonists that disrupt spermatogenesis in mice and have good oral bioavailability, potency, and other desirable drug-like properties. Our lead RAR? antagonist OR-812 is 155-fold and >1,000-fold more potent at RAR? than at RAR? and RAR?, respectively. Importantly, OR-812 disrupts spermatogenesis at oral doses of ~10 mg/kg following one week of treatment, without otherwise affecting the weight or appearance of the animals. In this two-year project, we propose to significantly de-risk translational development of OR-812 as a viable candidate for a male contraceptive by addressing these Specific Aims: 1) Identify a minimum efficacious dose (MED) for spermatogenesis inhibition by OR-812 following 45 days of oral dosing in mouse and establish reversibility within 2-4 months. 2) Determine the safety of OR-812 by non-GLP general toxicology in rat and find its NOAEL (No Observed Adverse Effect Level). 3) Confirm infertility following 45-day dosing of OR-812 and then restoration of fertility after a four-month recovery. The major project milestones are: (i) OR-812 has a good safety margin, a NOAEL that is >5x its MED for inhibition of spermatogenesis; and (ii) inhibition of fertility by OR-812 is reversible. Successful completion of this project will provide the data necessary for a pre-IND meeting with the FDA to elicit comments on Orphagen?s proposed IND-enabling pre-clinical study plan. With this information, we will apply for SBIR Phase III support to move OR-812 towards IND filing. Our long-term goal is to develop a non-hormonal male contraceptive that is safe, effective, and reversible. This would have significant social and economic impact by allowing men to share greater responsibility for contraceptive decisions.